The goal of the MSK SPORE in Lymphoma is to improve the cure rate of patients with diffuse large B cell lymphoma, through a collaborative effort between three New York City institutions: 1) Memorial Sloan Kettering Cancer Center (MSK), 2) Weill Cornell Medical College (WCMC), and 3) Herbert Irving Comprehensive Cancer Center (HICCC) of Columbia University. The overall approach for this SPORE in Lymphoma seeks to shift current treatment paradigms and clinical practice by introducing, developing, and applying new concepts, methods, and technologies to address several DLBCL subgroups with a clear unmet medical need. Our overall broad aims are: Specific Aim 1. To develop novel treatments for DLBCL based on targeting specific genetic and molecular alterations that contribute to the oncogenic process. Specific Aim 2. Identify potential biomarkers of antitumor efficacy using tissue specimens from patients enrolled on four clinical trials developed in the SPORE. We plan to identify and utilize biologic, genetic, and clinical biomarkers to select patients with DLBCL for novel therapeutic approaches. In Project 1, we will develop novel treatments to target the oncogenic cooperation between Myc and Bcl2. Such therapy can subsequently be evaluated in patients enriched for high Myc+/Bcl2+ expression in DLBCL using standard immunohistochemistry methods. These patients have a clear unmet medical need, as they have a poor prognosis with standard chemotherapy In Project 2, we will investigate the safety and clinical efficacy of genetically modified T cells to express chimeric antigen receptors (CARs) targeting CD19 in elderly patients with relapsed DLBCL who are not candidates for stem cell transplant.19 These patients have a dismal prognosis, with a median overall survival rarely exceeding one year.20 In Project 3, we will investigate the safety and efficacy of the first Tumor Enriched-Hsp90 (TE-Hsp90) inhibitor PU-H71 in patients with relapsed DLBCL.21,22 A novel PET-based molecular imaging using radiolabeled I-124 PU-H71 will be used to examine in vivo targeting of HSP90 by PU-H71, and to guide dosing and patients selection.23 Because c-Myc and intrinsic apoptosis pathway proteins are client proteins of TE-Hsp90, the efficacy of this treatment will be retrospectively assessed in patients with Myc+/Bcl2+ DLBCL. Finally, in Project 4, we will elucidate the normal and pathologic role of CBP and p300 in B cells, establish pre-clinical models for their therapeutic targeting, and test the activity of the novel HDAC inhibitor mocetinostat in a phase II clinical trial. we will use targeted sequencing strategies to select patients with DLBCL that carry mutations in the CBP/p300 histone acetyltransferase (HAT) genes for therapy with novel HDAC inhibitors.7-12 Our goal is to identify safe and active new agents in biomarker-defined patients with relapsed DLBCL.